Agent for treating Parkinson&#39;s disease comprising astrocyte function-improving agent as active ingredient

ABSTRACT

An agent for preventing and/or treating Parkinson&#39;s disease or Parkinson&#39;s syndrome, comprising, as an active ingredient, an astrocyte function-improving agent is disclosed. The astrocyte function-improving agent is preferably a compound represented by formula (I), a non-toxic salt thereof, or a hydrate thereof:  
                 
         R 5 , R 6 , R 11  and n are defined in the specification.

This is a continuation of application Ser. No. 09/906,065, filed Jul.17, 2001. The entire disclosure of the prior application, applicationSer. No. 09/906,065 is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Filed of the Invention

The present invention relates to remedies for Parkinson's disease.

More particularly, the present invention relates to an agent fortreating and/or preventing Parkinson's disease or Parkinson's syndrome,comprising, as an active ingredient, an astrocyte function-improvingagent represented by formula (I), a non-toxic salt thereof or a hydratethereof:

-   -   wherein the meaning of each symbol will be defined hereinafter.

2. Discussion of the Background

Parkinson's disease is a neurodegenerative disease which has beendesignated as one of specialization diseases by the Ministry of Healthand Welfare in Japan. Concerning the clinical symptoms of Parkinson'sdisease, there are observed three large characteristics, i.e., 1)tremor, 2) akinesia and 3) rigtidity. Since it was found that thedopamine content was reduced in the brain of patients with Parkinson'sdisease, it is considered that a decrease in dopamine in the braincauses Parkinson's disease. Therefore, the treatment of Parkinson'sdisease is carried out by administering dopamine with a form ofprecursor, regulating the dopamine metabolism or using dopamine agonist.

There have been known several remedies for Parkinson's disease, andtypical examples include L-dopa (dopamine precursor), dopamaineagonists, anticholinergic drugs, dopamine release promoters (amantadineetc.) and monoamine oxidase B inhibitors (selegiline etc.). However,these drugs suffer from some problems, such as a decline of the drugeffect after prolonged administration, side effects, a failure toprevent the progress of the disease and the like, and thus therapeuticbenefit obtained with antiparkinsonian drugs available at present isinsufficient.

Parkinson's syndrome means a group of nervous diseases includingParkinson's disease which exhibit conditions similar to Parkinson'sdisease (i.e., the three symptoms as described above).

On the other hand, it is stated in JP-A-7-316092 (the term “JP-A” asused herein means an “unexamined published Japanese patent application”)that compounds represented by formula (I) have effects of improvingbrain functions (in particular, astrocyte function) and therefore areuseful in treating and preventing Alzheimer's disease, amyotrophiclateral sclerosis, progressive supranuclear palsy, olivopontocerebellaratrophy, neuronal dysfunction by stroke or traumatic injury, multiplesclerosis, astrocytoma, meningitis, brain abscess, Creutzfeldt-Jakobdisease, AIDS dementia etc.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an agent forParkinson's disease.

This and other objects of the present invention have been attained by anagent for preventing and/or treating Parkinson's disease or Parkinson'ssyndrome, comprising, as an active ingredient, an astrocytefunction-improving agent.

DETAILED DESCRIPTION OF THE INVENTION

The astrocyte function-improving agent is preferably a compoundrepresented by formula (I), a non-toxic salt thereof, or a hydratethereof:

-   -   wherein R⁶ represents hydroxy, C1-4 alkoxy, C1-4 alkoxy        substituted with one phenyl, or —NR⁹R¹⁰,        -   wherein R⁹ and R¹⁰ each independently represent:            -   (i) hydrogen,            -   (ii) C1-4 alkyl,            -   (iii) phenyl,            -   (iv) phenyl substituted with C1-4 alkoxy or carboxyl,            -   (v) a 4- to 7-membered heterocyclic ring containing one                nitrogen atom, or            -   (vi) C1-4 alkyl substituted with phenyl,        -   C1-4 alkyl substituted with C1-4 alkoxy- or            carboxyl-substituted phenyl,        -   C1-4 alkyl substituted with a 4- to 7-membered heterocyclic            ring containing one nitrogen atom,            -   (vii) a 4- to 7-membered heterocyclic ring having 1 or 2                nitrogen atoms or a 4- to 7-membered heterocyclic ring                having one nitrogen atom and one oxygen atom, together                with the nitrogen atom to which they are bonded,            -   (viii) an amino acid residue together with the nitrogen                atom to which they are bonded;    -   (1) n is 1;    -   R¹¹ represents hydrogen; and    -   R⁵ represents (C1-10 alkyl in which one of the carbon atom(s) is        substituted with 1 to 3 fluorine atoms)—CH₂—,    -   with the proviso that R⁵ does not represent F—(CH₂)₅—,        F—(CH₂)₆—, F—(CH₂)₇— and F₃C—(CH₂)₂—; or    -   (2) n is 0 or 1;    -   R¹¹ represents hydrogen or chlorine; and    -   R⁵ represents:    -   C3-10 alkyl,    -   C3-10 alkenyl,    -   C2-10 alkoxy,    -   C2-10 alkylthio,    -   C3-7 cycloalkyl,    -   phenyl,    -   phenoxy,    -   F—(CH₂)_(m), in which m is an integer of 5 to 7,    -   F₃C—(CH₂)₂—,    -   (C2-10 alkyl substituted with 1 or 2 chlorine atoms)—CH₂, or    -   (C1-5 alkyl substituted with 1 or 2 substituents selected from        the group consisting of C1-4 alkoxy, C3-7 cycloalkyl, phenyl and        phenoxy)—CH₂—; or    -   R⁵ and R¹¹, taken together, form C3-10 alkylidene.

JP-A-7-316092 discloses that the compounds represented by formula (I)have an effect of improving astrocyte function and thus are effectivefor Alzheimer's disease etc. However, there is no described that thesecompounds are effective for Parkinson's disease and Parkinson'ssyndrome. Although the presence of reactive astrocytes was confirmed inParkinson's disease (Greenfield's Neuropathology, 6th edition, Graham DL, Lantos P L (eds), Arnold, London, 1997), it has not been decided sofar either these reactive astrocytes causes Parkinson's disease or areformed as the result thereof. It has been confirmed for the first timeby the present invention that the compounds represented by formula (I)are effective in an experiment in vivo (Parkinson's disease model).

In a preferred embodiment, the astrocyte function-improving agents foruse in the present invention are a compound of the formula (I) wherein nis 1, R11 is hydrogen, R5 is C3-10 alkyl and R6 is hydroxy and non-toxicsalts thereof.

In a more preferred embodiment, the astrocyte function-improving agentsfor use in the present invention are (R)-2-propyloctanoic acid andnon-toxic salts thereof. However, it is fully expected that not only(R)-2-propyloctanoic acid, which is a typical example of the compoundsaccording to the present invention, but any compounds represented byformula (I) are effective for Parkinson's disease because they have theeffect of improving the astrocyte function.

The compounds represented by formula (I) are publicly known per se orcan be produced by the method described in U.S. Patent Publication No.2003/0096802 A1, corresponding to JP-A-7-316092 or U.S. Pat. No.6,608,221, corresponding to WO 00/048982.

The compounds for use in the present invention can be converted into thecorresponding salts by publicly known methods. Non-toxic andwater-soluble salts are preferred. Examples of suitable salts includesalts of alkali metals (potassium, sodium etc.), salts of alkaline earthmetals (calcium, magnesium etc.) and salts of pharmaceuticallyacceptable amines (tetramethylammonium, triethylamine, methylamine,dimethylamine, cyclopentylamine, benzylamine, phenethylamine,piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine,lysine, arginine, N-methyl-D-glucamine etc.). The sodium salts areparticularly preferred.

The compounds to be used in the present invention can be converted intothe corresponding acid addition salts by publicly known methods.Non-toxic and water-soluble acid addition salts are favorable. Examplesof appropriate acid addition salts include inorganic acid salts such ashydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates andnitrates, and organic acid salts such as acetates, lactates, tartarates,oxalates, fumarates, maleates, citrates, benzoates, methanesulfonates,ethanesulfonates, benzenesulfonates, toluenesulfonates, isethionates,glucuronates and gluconates.

The compounds according to the present invention or salts thereof can beconverted into hydrates by publicly known methods.

Pharmacological Activity:

Because of having an effect of improving the astrocyte function, thecompounds of the present invention represented by formula (I) areefficacious in a Parkinson's disease model as will be describedhereinafter. Thus, it is expected that these compounds are effective forParkinson's disease and Parkinson's syndrome.

Toxicity:

It has been confirmed that the compounds of the present inventionrepresented by formula (I) have such low toxicity as being sufficientlysafe in using as drugs. When (R)-2-propyloctanoic acid was intravenouslyadministered to dogs in a single dose of 100 mg/kg, for example, no caseof death was observed.

Application to Drugs:

The astrocyte function-improving agents for use in the presentinvention, salts thereof or hydrates of the same are useful in treatingand/or preventing Parkinson's disease or Parkinson's syndrome.

For the purpose above described, the astrocyte function-improvingagents, a salt thereof, or a hydrate thereof may be normallyadministered to human or animal systemically or locally and orally orparenterally.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 0.1mg and 100 mg, by subcutaneous, intravenous or intranasal administrationup to several times per day, or by continuous administration between 1and 24 hours per day into vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered as innersolid compositions or inner liquid compositions for oral administration,or as injections, liniments or suppositories etc. for parenteraladministration.

Inner solid compositions for oral administration include compressedtablets, pills, capsules, dispersible powders and granules etc.Furthermore, they also include gargling agents and sublingual agents forintraoral insertion and adsorption. Capsules contain hard capsules andsoft capsules.

In such inner solid compositions, one or more of the active compound(s)are prepared as pharmaceuticals by known methods as they are, or bymixing with an inert diluent (lactose, mannitol, glucose,microcrystalline cellulose, starch etc.), connecting agents(hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium metasilicatealuminate etc.), disintegrating agents (cellulose calcium glycolateetc.), lubricating agents (magnesium stearate etc.), stabilizing agents,assisting agents for dissolving (glutamic acid, asparaginic acid etc.)etc. If necessary, the pharmaceuticals may be coated with a coatingagent (sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl cellulosephthalate etc.), or be coated with two or more films. Furthermore,capsules of absorbable materials such as gelatin are also included.

Inner liquid compositions for oral administration includepharmaceutically acceptable water agents, suspensions, emulsions,syrups, elixirs etc. In such liquid compositions, one or more of theactive compound(s) are dissolved, suspended or emulsified in inertdiluent(s) generally used (purified water, ethanol, mixture thereofetc.). Furthermore, the liquid compositions may also contain wettingagents, suspending agents, emulsifying agents, sweetening agents,flavouring agents, perfuming agents, preserving agents, buffer agentsetc.

Injections for parenteral administration include solutions, suspensions,emulsions, and solid injections which are dissolved or suspended insolvent(s) when they are used. One or more active compound(s) aredissolved, suspended or emulsified in solvent(s) when such compositionsare used. Examples of the solvents include distilled water for injectionand physiological salt solution, plant oil, propylene glycol,polyethylene glycol and alcohol such as ethanol etc., and mixturethereof. Such compositions may contain stabilizing agent, assistingagents for dissolving (glutamic acid, asparaginic acid, POLYSOLBATE80(registered trade mark) etc.), suspending agents, emulsifying agents,dispersing agents, buffer agents, preserving agents etc. They aremanufactured and prepared by sterilization at the final step or aseptictreatment. They may also be manufactured in the form of sterile solidcompositions, such as freeze-drying products, and they can be dissolvedin sterilized or sterile distilled water for injection or other solventbefore use.

Now, the present invention will be described in greater detail byreference to the following Examples. However, it is to be understoodthat the present invention is not construed as being limited thereto.

EXAMPLE 1 Improvement Effect of the Compound of the Present Invention inExperimental Model of Parkinson's Disease Induced by Administration ofMPTP

Male C57BL/6 mice (body weight: 20 to 28 g) were divided into groupseach having 6 to 12 animals. Without anesthetizing, MPTP (10 mg/kg;1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride) wasintraperitoneally administered to the mice 4 times at intervals of 1hour (Brain Res., 824: 224-231 (1999)). To the models thus prepared,Compound A of the present invention ((R)-2-propyloctanoic acid) wasadministered after 1, 6, 24 and 48 hours. Three days after the finaladministration, striata of the mice were collected. After weighing, thestriata were immediately frozen and stored. Then, dopamine content andDOPAC (3,4-dihydroxypyenylacetate) content were measured by HPLC in aconventional manner and evaluated. Table 1 shows the results.

Dunnett's multiple comparison test (both sides) was performed on thebasis of the data of the group with the administration of MPTP alone.

The values in Table 1 are shown by the average±the standard deviation.TABLE 1 Dopamine DOPAC content content (μg/g) (μg/g) Control 13.32 ±2.34** 2.50 ± 0.38** (physiological saline) Compound A of invention12.17 ± 1.41** 2.97 ± 0.49** 30 mg/kg MPTP  2.96 ± 2.07 1.40 ± 0.78MPTP + compound A  4.13 ± 1.48 1.30 ± 0.31 of invention 3 mg/kg MPTP +compound A  5.45 ± 2.00* 2.07 ± 0.77 of invention 10 mg/kg MPTP +compound A  6.75 ± 2.72** 2.26 ± 0.52* of invention 30 mg/kg*p < 0.05,**p < 0.01

Compared with the group of the administration of MPTP alone, the groupsof the administration of MPTP+the compound of the present inventionshowed significantly increased dopamine and DOPAC content depending onthe dose. The data of the group with the compound of the presentinvention alone were almost the same as the data of the control group,which indicates that it showed no adverse effect when used alone innormal animals.

Also, the compounds of the present invention are efficacious even inpost treatment administration, which makes them epoch-making drugsdifferent from the existing ones.

FORMULATION EXAMPLE 1 Preparation of Capsules

(R)-2-propyloctanoic acid (1 g) was encapsulated into gelatin capsulesto obtain 10 capsules each containing 100 mg of the active ingredient.

This application is based on Japanese application No. 2000-216763, filedon Jul. 18, 2000, the entire content of which is incorporated herein byreference.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof. All references cited hereinare incorporated, by reference, in their entirety.

1-7. (canceled)
 8. A method for increasing the content of dopamine in abrain, which comprises administering to a subject in need thereof aneffective amount of (R)-2-propylactanoic acid, a non-toxic salt thereof,or a hydrate thereof.
 9. The method according to claim 8, wherein thesubject is a patient in which the content of dop amine in the brain isreduced.
 10. The method according to claim 8, wherein the subject is apatient with Parkinson's disease or Parkinson's syndrome.
 11. The methodaccording to claim 10, wherein the Parkinson's syndrome is tremor,akinesia or rigidity.